Hand-held phase-shift detector for sensor applications

ABSTRACT

The invention is directed to a novel phase-shift detector capable of interfacing with an array of sensors. The detector is light-weight, portable and capable of fitting within the palm of a hand. The detector may be used in conjunction with a variety of diagnostic, biosensor and chemical sensor applications.

STATEMENT OF GOVERNMENT INTEREST

This invention was reduced to practice with Government support underGrant No. R01 EB000720 awarded by the National Institutes of Health andGrant No. CHE-0442100 awarded by the National Science Foundation; theGovernment is therefore entitled to certain rights to this invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a portable hand-held phase-shift detectorcapable of interfacing with piezoelectric microcantilever sensors (PEMS)and methods for using the detector and a system including the detector.The invention is particularly useful as a sensor or diagnostic device.

2. Description of the Related Technology

Biosensors and chemical sensors coupled with impedance analyzers arewell known in the art. For example, U.S. Pat. No. 6,278,379 and U.S.publication nos. 20060257286 and 20060217893 discloses sensor systemsincorporating an impedance analyzer to detect changes in resonancefrequency.

Current impedance analyzers, however, are typically bulky, heavy andrelatively immobile, thereby limiting the circumstances in whichresonance frequency may be measured. Although some impedance analyzers,such as impedance analyzers for determining the physical properties oflarge structures such as a building and impedance analyzers fordetermining body composition have been made portable, as disclosed byU.S. patent application publication no. 2005/0114045 and U.S. Pat. No.6,280,396, impedance analyzers for use with chemical sensors orbiosensors remain large, cumbersome and relatively immobile.

Therefore there is a need to develop a light, portable, hand-helddetector to facilitate diagnostic or sensor applications.

SUMMARY OF THE INVENTION

The invention is directed to a novel phase-shift detector capable ofinterfacing with an array of sensors.

In one aspect of the invention, the phase-shift detector is lightweightand portable.

In another invention, the phase-shift detector is a hand-held devicecapable of fitting within the palm of a hand.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1( a) is a schematic of the hand-held phase detector, oscillator,phase detector and relay component.

FIG. 1( b) is a photograph of the hand-held phase shift detectorinterfaced with an array of detectors for Bacillus anthracis spores.

FIG. 2( a) is a schematic of a hand-held phase-shift detector workingwith an array of PEMS capable of simultaneous detection of multipleantigens.

FIG. 2( b) is a photograph of a hand-held, portable phase-shift detector

FIG. 2( c) an optical micrograph of an array of four lead-magnesiumniobate-lead titanate solid solution (PMN-PT)/Cu PEMS.

FIG. 3 is a graph of resonance frequency shift versus time showing thedetection of Bacillus anthracis spores using a hand held phase-shiftdetector.

FIG. 4( a) is a graph of resonance frequency versus time showing thesimultaneous detection of three PEMS, one coated with scFv of HER2, onecoated with PSA antibodies and one coated with gp120 antibodies in a 23μg/ml HER2 solution.

FIG. 4( b) is a graph of resonance frequency versus time showing thesimultaneous detection of three PEMS, one coated with scFv of HER2, onecoated with PSA antibodies and one coated with gp120 antibodies in an 18μg/ml PSA solution.

FIG. 4( c) is a graph of resonance frequency versus time showing thesimultaneous detection of three PEMS, one coated with scFv of HER2, onecoated with PSA antibodies and one coated with gp120 antibodies in a 100μg/ml gp120 solution.

FIG. 5 is a graph of resonance frequency versus time showing a uniqueDMMP detection pattern.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention is directed to a portable hand-held phase-shift detector1, capable of simultaneously interfacing with and monitoring one or moresensors 7, as shown in FIGS. 1( a) and 1(b). Phase-shift detector 1comprises an oscillator 2, a phase detector 3, a relay component 4 and adisplay screen 5. The relay component 4 rotates the connection of phasedetector 3 and oscillator 2 among the connected sensors 7 in the sensorarray to enable phase detector 3 to measure the output of each sensor 7.

Oscillator 2 comprises a resonance circuit, including a transmissionline, a circuit substrate, chip components mounted on the circuitsubstrate, and an amplifying circuit for amplifying a resonance signalgenerated by the resonance circuit. Connected to sensors 7 by aconnection 6, oscillator 2 generates an input signal or voltage toactuate sensors 7. Oscillator 2 preferably actuates sensors 7 byinducing oscillation of sensors 7 in a frequency range that encompassesthe resonance frequencies of sensors 7 to enable detection of resonancefrequency shift of sensors 7 resulting from analyte binding.

Phase detector 3 measures the magnitude and phase shift of the outputvoltage of sensors 7 through a connection 8. A maximum in the phaseshift plotted versus frequency identifies the resonance frequency. Asignificant shift in resonance frequency indicates the binding of aparticular compound or molecule to the specific receptor on a sensorsurface, and thereby, verifies the presence of said compound or moleculein the environment being tested.

In one embodiment, oscillator 2 may be a microprocessor-controlledsignal generator. Phase-shift detector 1 may optionally include adisplay screen 5 for displaying results in any suitable manner such asin a numerical or graphical format. In a preferred embodiment,phase-shift detector 1 may also include a data transmitter fortransmitting data to an electronic information storage medium such as acomputer or computer disk. Display screen 5, or other suitable means,may function as an indicator which provides an indication of thepresence of a specific analyte. Alternatively, display screen 5 or othersuitable means may function as an indicator which provides an indicationif a specific analyte is present in an amount which exceeds a thresholdvalue.

As shown in FIG. 1( b), portable hand-held phase-shift detector 1 may beincorporated in, or work in conjunction with, any suitable sensorsystem. In a preferred embodiment, phase-shift detector 1 is associatedwith one or more piezoelectric microcantilevers (PEMS) or piezoelectricmicro-disks and enables detection of the magnitude and phase shift of anoutput voltage of each PEMS. Phase-shift detector 1 may be powered byany standard power source. In a preferred embodiment, the power sourceis portable, small and lightweight, such as a typical 9 volt battery.Hand-held phase-shift detector unit 1 may be about 3.5 inches by 7.5inches in size. Preferably, phase-shift detector unit 1 may besimultaneously connected to a plurality of sensors. In a preferredembodiment, phase-shift detector unit 1 is simultaneously connected tofrom about eight sensors to about thirty-two sensors. Preferably, theentire system is sufficiently small to be carried by a single person toa site of detection.

In a preferred embodiment, the hand-held phase shift detector 1 hasdimensions of up to about 7.5 cm deep by about 30 cm high by about 30 cmwide and weight of no more than about 2 kg and may simultaneouslyoperate as many as 32 sensors. The array sensors and their holder may beno larger than about 2 cm in width, about 2 cm in depth, and about 1 cmin height and weigh no more than 50 g. The phase-shift detector 1 mayfurther include a relay mechanism, such as a ribbon cable, forfacilitating connection 6 and connection 8. Preferably, the ribbon cableis less than 1 m long, less than 3 cm wide, and weighs less than 50 g.Preferably, the total weight of the system including hand held phaseshift detector 1 and sensors 7 is not more than 2.5 kg.

Advantageously small, the device is both portable and robust. In apreferred embodiment, the device may fit within the palm of a hand.Since the phase-shift detector is simple in design, it may be easily andinexpensively manufactured and may be made available as an off-the-shelfproduct for numerous applications. The phase-shift detector may be usedin biosensor, diagnostics or any molecular or chemical sensorapplications.

EXAMPLES Example 1

FIG. 2( b) shows one embodiment of a phase-shift detector, comprising anAnalog Devices AD8203 RF gain/phase detector IC as the measuring deviceand an Analog Devices AD9850 DDS Frequency Synthesizer as a highresolution microprocessor-controlled signal generator, in combinationwith an array of PEMS. The phase-shift detector of FIG. 2( a) is capableof monitoring at least 8 PEMS at the same time.

Example 2

FIG. 1( b) shows a phase-shift detector and an array of PEMS. Thehand-held phase shift-detector accurately detected the frequency shiftof each PEMS. FIG. 3 shows the results of an experimental study fordetecting Bacillus anthracis (BA) processed with the phase-shiftdetector of FIG. 1( b). The open circles represent PZT/glass PEMS with a2 mm long glass tip coated with antibody specific to BA spores, and theopen squares represent cantilevers coated with antibody specific to S.typhimurium and not specific to BA spores. The phase-shift detectoraccurately reported that the PEMS identified the presence of BA sporesfrom only the PEMS coated with antibodies specific to BA spores; bycomparison, the PEMS coated with antibodies specific to Salmonella didnot detect the BA spores. The results therefore demonstrate that thehand-held phase-shift detector is capable of generating accurate resultssimilar to those obtained by an impedance analyzer.

Example 3

A hand-held phase-shift detector in combination with an array of 3 PEMSwas used to detect the presence of various antigens. Each PEMS had adifferent receptor immobilized on its surface including, anti-gp120,anti-PSA, and scFv of Her2. gp120 is a surface protein on humanimmunodeficiency viruses (HIV). PSA (prostate specific antigen) is aprostate cancer marker, and HER2 is a member of the epidermal growthfactor receptor linked to breast cancer and other cancers and scFv is anengineered single-chain variable fragment receptor.

The PEMS were placed in 3 different solutions, each containing anantigen specific to each receptor. As shown in FIG. 4, the phase-shiftdetector correctly reported that only the PEMS having the antigenspecific receptor corresponding to the marker present in the solutionresponded when the array was submerged in each solution. FIG. 4( a)shows that only the PEMS with scFv to HER2 responded to HER2. FIG. 4( b)shows that only the PEMS with antibodies to PSA responded to PSA, andFIG. 4( c) shows that only the PEMS with antibodies to gp120 respondedto gp120. This experiment clearly illustrates that the phase-shiftdetector and PEMS array are capable of simultaneously detecting multipleantigens.

Example 4

The hand-held phase-shift detector, in combination with a PEMS array,may also be used to detect gases/chemicals. Unlike biological detectionwhere antibody-antigen binding is specific, most receptors forgas/chemical detection are not selective. By using a PEMS array havingdifferent receptors, it is possible to create a customized detectionpattern for a gas or chemical. The custom combination of the PEMS arrayincreases detection sensitivity and the accuracy of chemical or gasdetection. FIG. 5 shows a unique PEMS array for dimethylmethylphosphonate (DMMP), a nerve gas simulant.

Three lead magnesium niobate-lead titanate solid solution (PMN-PT)/CuPEMS are each coated with a different receptor which is immobilized onthe PEMS surface by microporous silica, mesoporous alumina and amonolayer of Cu²⁺ ions on a self-assembled monolayer of11-mercaptoundecanoic acid (MUA) to detect DMMP.

Having described the preferred embodiments of the invention which areintended to be illustrative and not limiting, it is noted thatmodifications and variations can be made by persons skilled in the artin light of the above teachings. It is therefore to be understood thatchanges may be made in the particular embodiments of the inventiondisclosed which are within the scope and spirit of the invention asoutlined by the appended claims. Having thus described the inventionwith the details and particularity required by the patent laws, theintended scope of protection is set forth in the appended claims.

1. A portable device for detecting a phase shift comprising: anoscillator for generating an input signal at a desired frequency, aconnection to said oscillator capable of providing an operativeconnection of said oscillator to at least one sensor, and a detectorcapable of detecting a phase shift of an output signal from a sensoroperatively connected to said oscillatory.
 2. The device of claim 1,wherein the device is capable of being operatively connected to an arrayof multiple sensors.
 3. The device of claim 2, further comprising arelay for selectively connecting said detector to each said sensors forselective receipt of the output signal from that sensor.
 4. The deviceof claim 1, wherein the oscillator is a microprocessor controlled signalgenerator.
 5. The device of claim 3, wherein the sensors are selectedfrom the group consisting of: piezoelectric microcantilevers andpiezoelectric microdisks.
 6. The device of claim 1, wherein the phaseshift detector is an RF gain/phase detector.
 7. The device of claim 1,wherein the total weight of the device is not more than about 2 kg. 8.The device of claim 1, wherein the device has a size of not more thanabout 7.5 cm in depth, by 30 cm in width and 30 cm in height.
 9. Thedevice of claim 1, further comprising an indicator that generates anindication of the presence of an analyte.
 10. The device of claim 1,further comprising an indicator that generates an indication of thepresence of an amount of an analyte that exceeds a threshold amount. 11.A portable system for detecting the presence of an analyte comprising:an oscillator for generating an input signal at a desired frequency, atleast one sensor capable of generating an output signal when providedwith an input signal, a connection from said oscillator to said at leastone sensor for providing said input signal to said sensor from saidoscillator, a detector capable of detecting a phase shift of an outputsignal from said sensor, and a connection from said sensor to saiddetector for providing said output signal from said sensor to saiddetector, wherein said system is sufficiently small to be carried by asingle person to a site of detection.
 12. The system of claim 11,comprising multiple sensors, a connection from said oscillator to eachsensor and a connection from each sensor to said detector.
 13. Thesystem of claim 12, further comprising a relay for selectivelyconnecting said detector to each of said sensors for selective receiptof the output signal from that sensor.
 14. The system of claim 11,wherein the oscillator is a microprocessor controlled signal generator.15. The system of claim 13, wherein the sensors are piezoelectricmicrocantilevers.
 16. The system of claim 11, wherein the phase shiftdetector is an RF gain/phase detector.
 17. The system of claim 11,wherein the total weight of the system is not more than about 2.5 kg.18. The system of claim 11, wherein the system has a size of not morethan about 7.5 cm in depth, by 30 cm in width and 30 cm in height. 19.The system of claim 11, further comprising an indicator that generatesan indication of the presence of an analyte.
 20. The system of claim 11,further comprising an indicator that generates an indication of thepresence of an amount of an analyte that exceeds a threshold amount.